Safer blood transfusions could result from Case Western Reserve University research on nitric oxide: Discoveries

Donated blood can lose the gas nitric oxide, as well as an enzyme that is essential to its oxygen-delivery function, quickly when it's stored. Replenishing the lost nitric oxide may improve the function of the blood in patients and help reduce the likelihood of organ damage and heart attack. Tim Boyle/Getty Images

CLEVELAND, Ohio--A blood transfusion can be a lifesaver when it’s really needed. But the widely-used procedure can often lead to poorer outcomes for patients than no transfusion at all — including heart attacks, kidney malfunction, immune reactions and even death. For many years it’s been unclear exactly why patients fare worse when they receive banked blood during surgeries or other procedures. Theories abound: excess white blood cells trigger an immune reaction in the patient; stored blood builds up toxins that trigger inflammation and raise the risk of stroke and heart attack; red blood cells become stiff and unable to squeeze through blood vessels; or the blood is depleted of something critical to its function in the body while being stored. “This is a major issue,” said Dr. Jonathan Stamler, Director of the Institute for Transformative Molecular Medicine at Case Western Reserve University, who has been studying the last of these possible causes in his lab. “These [bad effects] of banked blood were unexpected but are much more frequent than the viral infections that we’re used to thinking about as dangers of banked blood.” In 2007, Stamler and a team at Duke University (where he worked before coming to Cleveland in 2009) discovered that a gas essential for helping deliver oxygen to the body was depleted in banked blood. That gas, nitric oxide, or NO, is a short-lived chemical messenger that is carried by the blood protein hemoglobin, and it works to relax blood vessels. When there isn’t enough NO in the blood, it can’t do its job of getting oxygen to tissues. It was Stamler’s early research in the mid-1990s that established NO as equally important as oxygen and carbon dioxide to the function of blood. Now, Stamler and a team of researchers at CWRU and Duke have shown that a method for replenishing the missing NO in banked blood not only reverses the ill effects normally seen after transfusion, but may make giving blood to patients beneficial. The team published their results June 24 in the journal Proceedings of the National Academy of Sciences, or PNAS. “This is most impressive,” said Dr. Lawrence Goodnough, director of the transfusion service at Stanford University Medical Center, who was not involved in the PNAS paper. “I think it’s becoming increasingly apparent through Stamler’s work and other research that blood does several different things. It not only carries oxygen, but it also provides a source of NO that’s important for opening up the small blood vessels so that blood can move through and unload oxygen.” Blood transfusions are one of the most common medical procedures: about 24 million blood components, including red blood cells, plasma and platelets, are transfused annually in the United States. Of the 39 million patients discharged annually from U.S. hospitals, 2.3 million — or 5.8 percent — received transfusions, according to a May report in the journal Lancet by Goodnough and other researchers at Stanford University Medical Center. Many of these transfusions are likely unnecessary, recent research has shown. In 2010, a large study in the Journal of the American Medical Association showed a wide variation in transfusion rates for heart surgery patients at different centers across the United States, but little difference in death rates. In 2012, the Joint Commission and the American Medical Association targeted blood transfusions as one of the top overused procedures in the “National Summit on Overuse.” Increasing awareness, as well as the rise of “bloodless” techniques such as minimally-invasive surgeries, has helped produce a dip in the number of transfusions performed in many centers across the country. Since 2010, red blood cell transfusions at Goodnough’s center have dropped by 24 percent after implementing a computer system that prompts doctors to enter a reason for transfusion before administering banked blood to patients. Still, transfusions are often necessary and indeed, lifesaving. No one ever talks about a transfusion in terms of making a person better though, said Stamler. “We give it as infrequently as we can, and only in the hopes that it will keep someone from getting worse,” he said. “There’s no expectation that it will make you better, so we let people lose large amounts of blood before we intervene.” That may soon change, if Stamler’s recent work in animals proves successful in clinical trials as well. Stamler and his colleagues at Duke carried out their experiments on mice, rats and sheep, and they were able to demonstrate that banked blood low in NO is really bad at getting oxygen where it needs to go in the body. More critically, their treated blood, replenished with NO, improved blood flow, oxygen delivery and organ function in the animals. The team used a technique called renitrosylation to get NO back into the banked blood. “We’ve developed a small molecule, like a drug, that delivers NO to the hemoglobin,” said Stamler. The banked blood passes through a device where the drug is delivered before transfusion, he said. The researchers are able to measure how much NO is in the banked blood both before and after the drug treatment. Stamler is a co-founder of two companies developing NO related therapies — N30 Pharmaceuticals based in Boulder, Colorado, and Cleveland-based LifeHealth, but neither has licensed the renitrosylation therapy yet, he said. Stamler’s group found that in rodent blood, storage of only one day depleted the samples of NO by more than 70 percent. Giving this depleted blood to normal mice caused a drop in the amount of oxygen in their tissues, while blood that had been treated to restore NO did not. In a second set of experiments, sheep were subjected to bloodletting and then administered 14-day-old blood that was either untreated or replenished with NO. The sheep who received the treated blood had better cardiovascular measures including blood pressure and the volume of blood circulated per heartbeat. Also in sheep, the team was able to show that the treated blood reversed the kidney impairment that often happens as a result of transfusion, Stamler said. “It’s very similar to what you see in patients,” he said. “You see them having kidney problems and heart attacks. It makes sense when you see that blood flow to the kidney is going down, and if you put in the renitrosylated blood, that doesn’t happen.” “That may explain this observation of why patients who are heavily transfused with blood bank blood have multi-organ system failure, prolonged hospitalization and sometimes even mortality,” said Goodnough. “This is a mechanism that will help us sort out not only why blood bank blood may not be that helpful to patients, but why it may also be harmful.” Stamler said the next step for his lab is clear: clinical trials in people. “This is a major step for us. In the field we’re beginning to understand that It’s time that we demonstrated that blood [transfusions] actually improve oxygen delivery, and it’s very surprising to know that we haven’t done that yet.” Stamler and his lab have applied for funding from the National Institutes of Health for a study comparing the effects of renitrosylated blood transfusion to regular banked blood. Many research groups have shown the adverse effects of transfusion, but no methods for improving outcomes. “This is the first demonstration of any [therapy] to reverse the adverse effects, and that’s exciting,” Stamler said. Stamler’s said that using renitrosylated blood may also be beneficial for patients by improving blood flow and oxygen delivery, and may one day be used as a medical therapy to treat diseases, replacing the paradigm of transfusions as last ditch efforts to save lives. “Not only are we not seeing the adverse outcomes, but you’re seeing red blood cells do things that we’d attribute to an effective drug,” Stamler said. “We haven’t shown yet that it’s effective in people, but if it were, the effect would be quite large.”

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